A variety of diseases and trauma would defects of some tissues or organs and the loss of some or all functions, which are one of the major hazard we human beings are facing. Research and development of ideal materials for tissue repairing have become a major issue in the field of medicine, biological sciences and material science. The materials being widely used for tissue repairing in clinical medical are mostly un-absorbable artificial materials, which include polymer materials (such as polypropylene, PTFE, polylactic acid, poly glycolic acid, silica gel, etc.), metal materials (such as stainless steel, titanium and its alloys, etc.), inorganic materials (such as bioactive ceramic, hydroxyapatite, etc.) and composite material (carbon fiber/polymer, the glass fiber/polymer, etc.).
The structure and composition of the above material are far different from body tissues. The un-absorbable artificial materials can only act as an alternative and provide support in the short term. Un-absorbable artificial materials do not have the functions of promoting tissue regeneration and achieving organizational functions. Besides, after the implantation, artificial materials which cannot degrade remain in the body permanently if not surgically removed. Its stability, toxicity and carcinogenicity are difficult to control.
In some developed countries, implantable medical biomaterials are experiencing major industrial revolutions. Biodegradable and new biological materials which can induce tissue generation are taking the place of traditional non-absorbable materials. Based on principle of tissue engineering, extracellular matrix (extracellular matrix, ECM) material which uses animal tissues as raw material is the major trend. ECM is made up of many kinds of macromolecular substances such as collagen, the collagen glycoprotein, the composition such as amino glycan, proteoglycans, elastin, macromolecular substances are constructed in certain proportion form a complex three dimensional organic structure. The complex three dimensional organic structure provides suitable micro environment for the survival and activity of all kinds of cells, thus adjusting the cell growth, shape, metabolism, migration, proliferation and differentiation and regulation of tissue and organ function. A serious consequence due to tissue defect is a loss of “soil” (i.e. the losing of ECM), which is the main reason that the body itself cannot realize tissue repair and regeneration functions. Natural ECM can act as “soil” and is an ideal tissue repairing material for tissue regeneration. Removing the cell ingredient of animal tissue can result in the failure of most of the immunogenicity of the cellular elements, and the ECM components thus remain. An ideal tissue repairing material is then developed.
In clinical application abroad, there are cell-free ECM materials such as leather, pericardium, small intestine of animal origin products that are derived from animals such as pigs, horses and cattle. Among them, cell-free small intestinal submucosa (small intestinal submucosa, SIS) material is the most ideal soft tissue repairing material as is acknowledged in academia field. Cell-free SIS matrix material has the advantages below:
1) Low immunogenicity and high histocompatibility;
2) Special structure and composition to actively induce all kinds of tissue regeneration and form the biological basis;
3) Wide application field. It can be applied to various soft tissue repairing of human body;
4) Antimicrobial activity. The cell-free SIS substrate materials of American Cook Biotech Incorporated have clinical application of many samples in the abdominal wall repair, burns, anal fistula, refractory wound, plastic surgery, pelvic floor repair, tendon repair, genitourinary tract repair, nerve repair, and other fields.
There are lots of domestic and foreign patents and literature reports concerning the preparation of cell-free SIS matrix material, but only the company Cook Biotech incorporated cell-free SIS matrix material products in clinical application.
Cell-free process and inactivated virus process are the main processes and technical difficulties when it comes to preparing cell-free SIS matrix materials. The process requires a complete removal of virus in the small intestinal submucosa, cell composition and animal origin ingredient of DNA. At the same time, the process requires a complete reservation of the natural ECM composition and three-dimensional structure. In particular, the growth factors (such as alkaline growth factors, transforming growth factor, etc.) should be reserved to promote tissue regeneration. Reported method of cell-free and virus inactivated methods vary, but most of them cannot remove all the DNA ingredients of animal origin completely, are time-consuming and need to use a variety of organic solvent and high strength alkali, which leads to a destruction of the active composition of extracellular matrix cell-free SIS. Harmful solvent residues cause cell toxicity, thus altering the effect of tissue repairing. In addition, most of the technologies cannot take effective measures to control endotoxin residues. Cell-free SIS molding process is another technical difficulty of the preparation of matrix materials. In the molding process, the small intestine has only 6˜8 cm cross-section and the thickness of the small intestinal submucosa is less than 0.1 mm. It is difficult to produce tissue repairing products that are of different size and thickness, and which can be adapted to different requirements of mechanical strength. Cook Biotech Incorporated uses the method of vacuum pressing molding. This method compresses the space structure of decellularized SIS matrix material and destroys the natural ECM's three-dimensional structure, thus influencing the porosity of this material.
A clinical study has shown that the cell-free SIS matrix material products (surgisis BIODESIGN etc.) produced by Cook Biotech Incorporated caused syndromes in the clinical application such as serious swelling, infections, immune rejection, and complications such as poor healing of organization. Among those syndromes, the highest occurring is swelling. Complications may lead to disease recurrence or even to a need of a second operation to remove cell-free SIS matrix materials which have already been implanted. Studies have proven that serum swelling is caused by Th2 inflammatory cytokine responses, and the reaction is closely related to the products of animal origin residual DNA.